Alzheimer’s Disease: The Genetics and Effects of A Silent Killer
It is widely known that genes play a complex role in every living being in our world. More technology, the human genome project, and increased public interest in the subject of how genes affect our bodies and our lives have led to leaps and bounds in the amount of understanding that we have about the role of genetics in our human affairs. Recently, much attention has been given to the Beltway Sniper, but there is another such deadly, silent, and elusive killer that will be directly involved in the lives of more than 10% of those 60 and older and nearly 50% of those 85 and older: Alzheimer’s Disease (AD) (Alzheimer’s Association). Alzheimer’s is a progressive, degenerative disease of the brain, and the most common form of dementia. It attacks the brain resulting in impaired memory, thinking and behavior. Scientists have still been unable to pinpoint a gene that causes Alzheimer’s disease. For more than 5 million Americans there is no cure, and only recently have the advancements in treatment been valuable enough to mention.
The two basic types of AD are familial (FAD) and sporadic (SAD). More than one gene mutation can cause AD, and there are genes on more than one chromosome that are involved. Sometimes a single does of a gene is enough to have AD and sometimes two genes (one from each parent) are needed. FAD is a much rarer form of AD that occurs in a little less than 10% of victims (Alzheimer’s Disease Education and Referral Center). Mutations in at least three different genes are responsible for early-onset FAD and show nearly 100% penetrance with autosomal dominant inheritance. It is associated with genetic mutations in the amyloid beta precursor protein (APP) gene on chromosome 1, (PS-1) gene on chromosome 14, and presenilin-2 (PS-2) gene on chromosome 21 (Helisalmi). Some of the earliest theories about Alzheimer’s were formed from autopsies, where a microscopic change in the brain occurs leaving certain easily identified clues as "senile plaques" and "neurofibrillary tangles" (Jorm 21). Senile plaques occur in areas of the brain containing axons and consist of the core protein amyloid. This protein does not occur naturally in the brain and is surrounded by debris from degenerating neurons. Neurofibrillary tangles do occur naturally in cell bodies of neurons and consist of long thread-like structures. The threads are filaments twisted around each other in pairs to make a helix. The filaments play a role in transporting essential chemicals from around the cell body to distant axons (Jorm 23). They appear most frequently in the hippocampus and cerebral cortex of the brain. The hippocampus is known to be vital in memory recall. Alzheimer’s patients have missing or damaged nerve cells connecting the hippocampus to other areas of the brain (Jorm 26). The cortex is vital to much of our intelligence and damage to the cortex commonly results in problems with language, performance of actions on command, and recognition of familiar objects: classic Alzheimer’s symptoms (Jorm 27). One theory would be that when they become tangled it creates an interference with the transport and thus impairs the brain’s functions and memory. Both senile plaques and these tangles occur in the elderly but are noted to be much more common with those experiencing memory loss and those with Alzheimer’s disease.
Though genes alone are not all-powerful, if the proteins that they produce contain one or more mutations in the DNA, the results can be fatal. There has been much attention given lately to a possible link between apolipo protein E (apoE) gene and AD. Sporadic AD (the type of AD that begins affecting victims at a later age) appears to be related to the apoE gene found on chromosome 19. According to the Alzheimer’s Disease Education and Referral Center, ApoE comes in several alleles, but the most common forms of the gene are apoE2, apoE3, and apoE4. We each inherit one allele from each parent and people with the E3/E4 alleles are affected by both. Having one or more copies of the E4 allele put a person at a higher risk for AD, but does not make it certain that the person will, in fact, have the disease. Chromosomal alterations have long been thought to contribute to Alzheimer’s disease. In 1972 researchers noted that the presence of large acrocentric, chromosomes with the centromere closer to one end, marker chromosomes in Alzheimer patients. In a follow up study it was noted that there was a much higher number of fragmented chromosomes in AD patients compared to other elderly subjects. All had at least one, and 7/10 had two or three in each cell. It is suspected that these were prematurely separated X chromosomes (Reisberg 163).
Further chromosomal evidence comes from the startling number of those with Down Syndrome (containing a trisomic dose of chromosome number 21) who develop Alzheimer’s. In fact, 25% of adults with Down Syndrome develop the disease by age 40, and the rate sky-rockets to 65% after age 60 (Dymkowski). In a 1997 article published by Harvard, researcher Huntington Potter went so far as to claim that all Alzheimer’s cases are created by the trisomy 21 even though the general population only has the normal amount. Most cases of the familial form of Alzheimer’s disease have been linked to mutations in either of two related genes, presenilin 1 and 2, but it was not known what the purpose of these two genes were. Huntington and his team tracked down the proteins produced and determined that they were in the nuclear membrane, on the kinetochores, and centriomeres, which are very specialized and delicate structures that are vital in cell-cycle regulation and chromosome segregation during mitosis. Their findings suggest that this segregation could be the underlying cause of the FAD form of Alzheimer’s disease. If indeed the presenilin proteins are involved in mitosis, then their mutant forms could cause problems in segregation, producing an irregular number of chromosomes. Since chromosome 21 contains the amyloid precursor protein (APP), and fragments of APP accumulate in the deposits found in the brains of people with Alzheimer’s, this extra dose of chromosome 21 could produce more APP and make the occurrence of Alzheimer’s more likely. Huntington explains:
Indeed the results of an investigation that compared skin cells from normal patients and those with Alzheimer’s, the AD patients had more than twice the frequency of trisomy 21. In addition to inducing cell suicide, abnormalities in the number of chromosomes promote inflammation in the brain. This inflammation can lead to neuronal cell death. Brain cells known as astrocytes and microglia continue cell division throughout life and therefore would be particularly sensitive to missegregation (Huntington).
Part B:
I became interested in researching Alzheimer’s disease because of its effects on my grandfather Harold S. Lusk. He has always been a source of constancy and refuge in my years of growing up. Our houses are separated by about one half of a mile that is easily navigated by a trail through the woods that we built together when I was five. He was a deacon in our church, a Sunday school teacher for almost twenty years, and helped coordinate the Homebound Ministry. When he rose to speak or pray in church, there was immediate silence, an understood air of respect and admiration that settled down over those in attendance. He spoke elegantly and fluidly with a voice that was clear and confident. Over the past 3-4 years, however, his health has deteriorated. The most marked changes can be noted in his speech, memory, and mental alertness. These are classic symptoms of Alzheimer’s disease and the more I have researched and spoken with my grandmother, the more I am confident that he most likely has AD.
I can remember sitting in my grandparents’ living room as a child, huddled close the wood stove as my grandfather would light up and tell stories to a room full of grandchildren, cousins, and friends. At Christmas, there would always be a familiar gathering and he would bring that old worn out black Bible and before any presents could be opened, we would hear the Christmas story. It takes a lot to command the attention of a group of 4-5 children and early teenagers, but I can remember listening intently, my gaze transfixed and interest captivated by the words spoken with such intensity and devotion. This past Christmas marked the first ever in my 19 years that that Bible was held by different hands. He stayed home. The mood was somber. The eyes were lowered, and the air hung heavy with the realization that something was entirely different this year. My grandmother says that, though he will not admit it and instead blames the arthritis and his cane, he is embarrassed and shy that he sometimes gets lost in conversations. We must, politely and gently, remind him several times what we are talking about. His concentration falters and words seem to get stuck somewhere inside. To look into his tired eyes and see that he has something he desperately desires to convey, but can’t string together the right words to make his point, brings a lump to my throat even now.
There are scary times when he becomes completely lost and a dark haze forms over his clear blue eyes. These small attacks have been labeled Transient Ischemic Attacks (TIA’s). Upon speaking to my grandmother about these TIA’s, I learned that they are attributed to buildups of plaque or bundles of disconnected arteries at the base of the skull that do not allow oxygen to flow properly into the brain. While there has been no clear diagnosis of his problem, these dark splotches in the brain appear strikingly similar (John Douglas French Center for Alzheimer’s Disease) to the "senile plaques" and "neurofibrillary tangles" that were described in Part A. There is no history of AD in our family, and thus I conclude that if it is indeed AD, he has the sporadic form of the disease also described in the previous section.
When the general public thinks of Alzheimer’s one name undoubtedly comes to mind: President Ronald Reagan. The man who won the greatest electoral landslide in history carrying 49 of 50 states, "The Great Orator", the man who united a country, brought back a sense of national pride, and won the cold war. In a sad irony, The Great Orator has now fallen into the same lonely path that my grandfather has begun to enter. In her biography When Character Was King Peggy Noonan describes him now:
According to the Alzheimer’s Association, the only national voluntary health organization dedicated to funding research for the prevention, cure and treatment of Alzheimer’s disease, the annual cost of Alzheimer care in the United States is at least $100 billion. Worse yet, health insurance and Medicare do not pay for the long-term care that most patients will require and long-term care insurance must be purchased before the onset of the illness. This is one problem that our family has just begun to think about. The cost and practicality of long term care for the elderly is always a difficult situation for any family, but this is compounded by the extra care that Alzheimer’s patients need. More than 75% of those with Alzheimer’s live at home. Though it may sound callous to put a price on human suffering, AD has a very real economic cost not only to family members but to the nation. The average lifetime cost of the disease per patient is $200,000. Alzheimer’s disease costs American business $33 billion annually - $7 billion toward the total cost of care, plus $26 billion in lost productivity of caregivers. In speaking to my grandmother I was completely astounded by the number of medications that my grandfather was taking and even more shocked by the bottom line cost that she pays per month.
The political aspects of Alzheimer research and funding are also a very interesting topic. United States Senator John D. Rockefeller IV noted this in a speech in January 2002:
It is sad, even if it is predictable, that drug companies are more concerned with profit than the persons afflicted. Still, rightly or not, the government often steps in to disrupt the purely capitalistic system in instances of human suffering. So what is the government doing to combat this problem? When looking at the comparison of spending on research, the answer is simple: not enough. Alzheimer arrives in at number nine in the top ten, receiving 466 million dollars per year of funding. In contrast AIDS receives 2.1 billion dollars per year. Now using the same National Health Institute statistics 950,000 Americans are infected with the AIDS virus, while 5 million have Alzheimer’s. That comes out to be $2,210.53 per person infected with AIDS, and only $93.20 per person infected with Alzheimer’s. That means that the AIDS disease receives almost 24 times more funding per person afflicted than Alzheimer’s. I dare not try to expound on the reasons for this shocking statistic. That would be an entirely different paper perhaps discussing the way the elderly are viewed in our Western Civilization where youth is so glamorously praised, governmental pandering of our tax dollars to special interest groups, or the other various government programs that could easily be eliminated to provide this much needed funding.
In fact in a recent survey, medical research funding was ranked as the second most important form of government spending, behind only education. An overwhelming number of Americans, 95%, say Alzheimer’s disease is a serious problem facing our nation. A majority, 57%, indicate that they are personally concerned about getting the disease, an increase of ten percentage points from a decade ago, according to a new poll. Another interesting finding is that 64% of Americans age 35 to 49, the baby boomers, are concerned about getting the disease, even though the onset would, in reality, be decades away. Alzheimer’s Association interim President Stephen McConnell described the poll saying:
Perhaps this increase in interest is due to a rise in the number of people indirectly affected by the disease. More than four of ten people surveyed say that they know someone currently suffering from Alzheimer’s and about one of five says that someone in their immediate family is living with Alzheimer’s. Another note worthy statistic was that three of four Americans say that they are more concerned about a family member contracting the disease than developing it themselves (AlzheimerSupport.com).
Indeed, more than the social consequences, more than the issue of political funding, more than the genetic secrets, the real and lasting effects of Alzheimer’s are transcribed out in the lives of those who have to sit by helplessly and watch their loved one wither and mentally disintegrate from AD. Numerous memoirs chronicle the grief, the desperation, and the frustration of caring for a loved one with AD. Books such as Cup Full of Tears, A Long Goodbye and Beyond, and Forget-Me-Not: Caring for an Alzheimer’s Patient journal the daily struggles of the caregiver and the anxieties associated with the work. My grandmother has spoken to me extensively regarding the pressure that it puts on her personally. She has been forced to give up much of her involvement in our church, community, and she rarely makes it up for Sunday dinners which used to be quite regular. My grandfather also understands that his care has increased the work load for her. She told me during our conversation, "He cries at least a couple times a week, Hal. He keeps telling me that he feels like a burden. Says he’s outdone his welcome. And well, I just say to him, Harold, now if it was me in your position do you think that you’d do anything differently towards me?" Of course they both know the answer to that question.
While this seems like the best suited and most loving solution for some families it is not so simple. Often times the mate of the afflicted person is either too untrained or sick them self to put in such an effort. It then becomes what Rosemary Bland refers to as "a social disease with responsibility undertaken by local authorities within the context of community care" (Bland 69). Nursing home facilities and assisted living puts an increased economical strain on the family, but is often times the only feasible solution. Bland is skeptical of the assisted living aspect of care because of the degree of attention that is needed for these, at times, highly unstable patients. In her report "On the Margins: Care Management and Dementia" she reviews a pilot care project in Scotland called the Elderly People in the Community (EPIC) which discusses the difficulties care givers looking after someone with dementia experience. She summarizes that there were disappointing results for the care givers looking after someone with dementia as opposed to someone without. She goes so far as to suggest that "some doubt is cast on the effectiveness of care management in avoiding institutionalization of people with dementia and the appropriateness of promoting long-term care at home rather than high quality institutional care" (60).
Still other studies suggest that the familiarity and comfort of home can help calm some of the anxiety and stress that Alzheimer’s patients can undergo. Some of the symptoms of AD include mood swings (sometimes violent), bouts of depression, and feelings of isolation. People with Alzheimer’s often develop patterns or repeat activities that they find comfortable and enjoyable, giving them a familiar setting with familiar objects, smells, and sounds can ease or prevent some of the worse side effects of AD. There are many basic tips to creating a safe and beneficial environment at home for the patient. One suggestion in common to several of the websites and books I looked through, is to create a "respite zone" where the care giver can simply get away from the stress of such a demanding job. Ageless Design says, "Burn out is a big problem for caregivers and there needs to be a place where one can get away, relax and have time alone while someone else provides care." My grandmother says that she sets a certain time each day to get out and go for a walk, or she will go work at our church to get some fresh air and a break from the demands of being "on call."
There is simply no easy solution for Alzheimer’s disease. Researchers struggle with the compounding effects of different genes on different loci, the multiplicity of side effects, and the inconsistencies in modern theories. Society struggles with the burden of expensive research, loss of production in workers, and determining how to best help the millions of patients. Families struggle with finding the best care, determining how to provide for the person’s special needs, and dealing with slowly losing a family member. Still there is hope. Public awareness is increasing, early detection is becoming easier, and with all the new technology and brilliant minds behind it there could be a cure right around the corner. It’s too late for my family however, and there will probably once again be an empty seat around the Christmas tree this year. But in that circle of friends and family, in the prayers lovingly offered toward the December skies, in the love that binds a family together like no other force in the universe, the memory of Harold S. Lusk will forever burn brightly no matter how his physical or mental flame may flicker. I know the next time I see him and say, "Well hey Pop, how yah doin’?" He will undoubtedly smile, look up toward heaven for a moment, and then answer the same way he has a thousand times before, "Dead men don’t talk. It’s the best day of my life."
I am particularly fascinated with the 18- to 49-year old response. With so many competing national priorities that directly affect them, from military conflict to a troubled education system, they place a stunningly high priority on Alzheimer’s disease…We must act now and invest in research programs. A small investment today will save this nation billions of dollars and save families incalculable emotional costs in the future. This poll indicates that the American public wants action (AlzheimerSupport.com).
Despite the fact that there are roughly similar numbers of Alzheimer’s patients and cancer patients, pharmaceutical companies have many more cancer medicines in the pipeline and on the market. They understand how cancer research can be applied, and so they can see the potential for return on their investment in new cancer drugs.
He’s a sick old man now and lives in a house in his beloved California. There are those who feed him and see to his safety and make sure he isn’t awake without their knowledge; there’s a mat on the floor next to his bed that is rigged to let them know if he gets up. He doesn’t speak much anymore, can’t converse, isn’t really there. And still with all that, he’s so hardwired for courtesy, for a regard for others, that w hen he accidentally bumps the arm of the woman feeding him, he will say with perfect enunciation, "Oh, I beg your pardon madam." And whoever is with him will be startled because it’s as if he’s there, and taking part (15).
…instead of occurring in every cell of the body because the chromosome segregation went wrong during the development of the egg, it occurred during the growth of the individual, so only a small percentage of cells had three copies of the chromosome. This would then cause Alzheimer’s disease, but at a later stage because of the fact that you only have a few cells in the body that have this genetic defect…
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